2-heterocyclic amino derivatives of 10&#39;,11&#39; - dihydrospiro cyclopropane-1,5&#39;-5h-dibenz(a,d)cycloheptene



United States Patent 3,522,259 Z-HETEROCYCLIC AMINO DERIVATIVES 0F10,11' DIHYDROSPIRO CYCLOPROPANE- 1,5'-5H-DlBENZ(a,d)CYCLOHEPTENE CarlKaiser, Haddon Heights, N.J., and Charles L. Zirkle, Berwyn, Pa.,assignors to Smith Kline & French Laboratories, Philadelphia, Pa., acorporation of Pennsylvania N0 Drawing. Original application Oct. 19,1965, Ser. No. 498,151, now Patent No. 3,423,461, dated Jan. 21, 1969.Divided and this application Aug. 23, 1968, Ser.

Int. Cl. 007d 51/70 U.S. Cl. 260268 7 Claims ABSTRACT OF THE DISCLOSUREHeterocyclic amino derivatives of 10,11'-dihydrospiro [cyclopropane-l ,5-H-dibenzo a,d cycloheptene] wherein the dibenzocycloheptene ring may behalogen, trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthiosubstituted have antidepressant activity. The compounds are generallyprepared via the ,11-dihydrospiro[cyclopropane 1,55H-dibenzo(a,d)cycloheptene]-2-carboxylic acids.

FORMULA I in which:

R represents hydrogen, halogen such as chlorine or bromine,trifiuoromethyl, lower alkyl such as methyl, lower alkoxy such asmethoxy or lower alkylthio such as methylthio, preferably in the3-position of the dibenzocycloheptene portion of the ring system.

It represents an integer from 0 to 2; and

R and R when taken together with the nitrogen atom to which they areattached, represent a heterocyclic amino group containing up to carbonatoms, for example a pyrrolidine, piperidine, N-methylpiperazine, N'-B-hydroxyethyl) -piperazine or N- fi-acetoxyethyl) piperazine ring.

The nontoxic pharmaceutically acceptable acid addition salts of thecompounds of Formula I are also included within the scope of thisinvention. Both organic and inorganic acids can be employed to form suchsalts, illus- 3,522,259 Patented July 28, 1970 trative acids beingsulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic,tartaric, pamoic, ethanedisulfonic, sulfamic, succinic,cyclohexylsulfamic, famaric, maleic, benzoic and the like. These saltsare readily prepared by methods known to the art.

The compounds of this invention when R in Formula I above is differentfrom hydrogen may be present as cistrans isomers due to the geometricalarrangement of the dibenzocycloheptene ring substituent and the aminomoiety with respect to the spiro ring system and further as d, 1 opticalisomers. Unless otherwise specified in the description and accompanyingclaims, it is intended to include all isomers, whether separated ormixtures thereof.

The novel 10',11' dihydrospiro[cyclopropane-l,5-5H-dibenzo(a,d)cycloheptenes] of this invention are prepared by severalmethods, the choice of which depending on the definition of n. Thestarting materials for these methods The novel l0,l1dihydrospiro[cyclopropane-1,5-5H- dibenzo(a,d)cycloheptene]-2-carboxylicacids having the formula:

F ORMULA II in which R is as defined in Formula I. These compounds areprepared from appropriate 10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ones which are known in the art. Thus, thedibenzocycloheptenone is reacted with a lower alkyl lithium, preferablymethyl lithium, to give the 5- methyl-S-ol derivative which isdehydrated, advantageously by heating in a dimethylsulfoxide solution,to give the corresponding 10,11-dihydro-5-methylene-5H-dibenzo[a,d]-cycloheptene. The latter is reacted with ethyl diazoacetate togive an ethyl 10',1l'-dihydrospiro[cyclopropane 1,5 5Hdibenzo(a,d)cyclohepten]-2-carboxylate which is hydrolyzed with alkalito give the carboxylic acid of Formula II. When the dibenzocycloheptenering is substituted by other than hydrogen as defined by R above, amixture of isomeric carboxylic acids is obtained which can be separatedby fractional crystallization.

The useful compounds of Formula II are converted to amino compounds ofthis invention by several routes. Reaction of the carboxylic acid witheither a thionyl halide or a lower alkyl haloformate gives thecorresponding acid halide or lower alkyl mixed anhydride which is thentreated with a heterocyclic amine to give a 2-carboxamido 10',11'dihydrospiro[cyclopropane-1,5-5H- dibenzo(a,d)cycloheptene]. Reductionof the amide with, for example, lithium aluminum hydride gives thecorresponding Z-heterocyclic aminomethyl derivatives of Formula I.

The novel compounds of the invention represented by Formula I abovewhere n is 2 are prepared by similar reaction of the carboxylic acid ofFormula II with either a thionyl halide or a lower alkyl haloformate togive the corresponding acid halide or lower alkyl mixed anhydride whichis then treated with diazomethane to yield a 2 diazoacetyl 10',11'dihydrospiro [cycl0propane-1,5- SH-dibenzo(a,d)cycloheptene]. Amethanolic solution of the latter is rearranged with silver benzoate togive the methyl l0,11' dihydrospiro[cyclopropane 1,5 5H- dibenzo (a,d)-cycloheptene] -2-acetate which is hydrolyzed with alkali to give theZ-acetic acid derivative. Conversion of the acid to either an acidchloride or lower alkyl mixed anhydride, followed by reaction with aheterocyclic amine to give a2-acetamido-l0',ll'dihydrospiro[cyclopropane-1,5-5H-dibenzo(a,d)cycloheptene] and reduction of the amide with, forexample, lithium aluminum hydride yields the Z-heterocyclic aminoethylproducts of Formula I.

Alternatively, the diazoketone above is rearranged with silver oxide inthe presence of an amine to give the acetamido derivative directly whichis then reduced to the Z-heterocyclic aminoethyl products.

To prepare the compounds of Formula I Where n is O, the carboxylic acidof Formula II is converted to either an acid halide or a lower alkylmixed anhydride as described above and this derivative is then treatedwith sodium azide to give the corresponding acid azide. The acid azideis thermally decomposed by heating in an inert organic solvent to givethe corresponding isocyanate. The resulting isocyanate is hydrolyzedwith a mineral acid such as hydrochloric acid or an alkali metalhydroxide such as sodium or potassium hydroxide at elevated temperaturesto give a primary amine derivative. The pyrrolidinyl and piperidinylderivatives of Formula I above are prepared from the primary amine and1,4-dibromobutane and 1,5- dibromopentane, respectively, in an organicsolvent refluxing at a temperature from 100-150 C. and in the presenceof potassium carbonate. Similar reaction of the primary amine withmethyl bis-(B-chloroethyDamine gives the N'-methylpiperazinylderivative.

The novel compounds of this invention may be administered orally orparenterally in conventional dosage forms such as tablets, capsules,injectables or the like, by incorporating the appropriate dose of acompound of Formula I with carriers according to accepted pharmaceuticalpractices.

The foregoing is a general description of the main synthetic routes inthe preparation of lO',l1'-dihydrospir0cyclopropane-1,5-5H-dibenzo(a,d)cycloheptenes] of this invention. Itwill be readily apparent to one skilled in the art that variations ofthese procedures are possible. The following examples illustrate theseprocedures but should not be construed as limiting the invention to thespecific compounds prepared thereby. Where isomers can exist, theexamples are intended to read on the similar employment of eitherisomer.

PREPARATIONS (A) l l'-dihydrospiro [cycl0propane-1,5 '-5H-dibenzo(a,d)-cyclopetene]-2-carboxylic acid To 300 ml. of a 5.21% solution ofmethyl lithium in ether (approximately 11.1 g.) is added slowly withstirring a suspension of 45.7 g. of 10,11-dihydro-5H-dibenzo[a,dJcyclohepten-S-one in 200 ml. of ether. The solution is stirred andrefluxed for two hours and then poured slowly into 1 l. of ice-water and50 ml. of concentrated hydrochloric acid. The separated aqueous layer isextracted with ether and the combined dried extract is concentrated invacuo to give 10,1l-dihydro-S-methyl-SH- dibenzo[a,d1cyclohepten-S-ol,M.P. 135138 C.

A mixture of 45.9 g. of the above alcohol and 100 ml. ofdimethylsulfoxide is heated at 173 C. for hours. The solution is allowedto cool, poured into 750 ml. icewater and extracted with ether. Thedried extract is concentrated to give10,11-dihydro-S-methylene-SH-dibenzo- [a,d] cycloheptene, M.P. 66-685 C.

To a refluxing and stirred suspension of 1.0 g. of cupric sulfate powderin 500 ml. of dry toluene is added dropwise a solution of 38.7 g. of theabove S-methylene compound and 28.5 g. of ethyl diazoacetate in 500 ml.of dry toluene. The resulting mixture is refluxed for minutes afteraddition is completed, filtered and the filtrate is concentrated invacuo. The residue is distilled to give ethyl 10,l1' dihydrospiro[cyclopropane-l,5'-5H-dibenzo(a,d) cycloheptene]-2carboxylate, B.P.range ISO-190 C./ 0.5-1.5 mm.

To a solution of 52.8 g. of the above earboxylate in 500 ml. of ethanolis added a solution of 33.6 g. of potassium hydroxide in ml. of waterand the resulting solution is stirred and refluxed for two hours. Thecooled reaction mixture is diluted with water and ether and theseparated aqueous layer is washed with ether, then acidified withconcentrated hydrochloric acid and extracted with ether. The extract iswashed with saturated sodium chloride solution, dried and evaporated invacuo to give 10',11-dihy drospiro[cyclopropane 1,5SH-dibenzo(a,d)-cycloheptene]-2-carboxylic acid, M.P. l97-200 C.

(B) 10',11'-dihydrospiro[cyclopropane-1,5-dibenzo a,d) -cycloheptene]-2-acetic acid A mixture of 10.0 g. of10,1l-dihydrospiro[cyclopropane-l,5'-5H-dibenzo(a,d)cycloheptene]-2-carboxylicacid and 10 ml. of thionyl chloride is allowed to stand at roomtemperature for one hour, then is heated at reflux for 15 minutes. Thesolution is concentrated in vacuo and the residue stripped with toluene.The residual acid chloride is then dissolved in 50 ml. of ether and theether solution is added to a solution of diazomethane in 400 ml. ether(prepared by addition, in portions, of 23.2 g. of N-methyl-N-nitro-N-nitrosoguanidine to a mixture of 60- ml. of 50% potassiumhydroxide solution and 150 ml. of ether at 0 C., decantation of ethersolution, extraction of aqueous portion with ether, and drying of ethersolution). The reaction mixture is allowed to stand at room temperaturefor 12 hours and filtered to give 2-diazoacetyl- 10,1l'dihydrospiro[cyclopropane-1,5-5H-dibenzo(a,d) cycloheptene], M.P.164-l65 C. (d.).

To a stirred suspension of 2.9 g. of the above diazoketone in 30 ml. ofmethanol is added a solution of 0.3 g. of silver benzoate (prepared byreaction of equimolar quantities of sodium benzoate and silver nitratein an aqueous medium) in 3 ml. of triethylamine. The mixture is stirredat room temperature for 15 minutes, then refluxed for one hour, filteredand the filtrate concentrated in vacuo. The residue is suspended inwater, extracted with ether, and the dried extract concentrated to givethe methyl ester of the acetic acid derivative.

To a solution of this ester in 25 ml. of ethanol is added a solution of1.0 g. of potassium hydroxide in 5 ml. of water. The mixture is stirredand refluxed for one hour, then concentrated in vacuo. The residue isdissolved in water and extracted with ether. The aqueous portion is madeacidic with acetic acid, extracted with ether and the dried extractconcentrated. The residue is extracted with hot hexane, the driedextract concentrated and the residue recrystallized from aqueous ethanolto give 10',ll'-dihydrospiro[cyclopropane-l,5 5H dibenzo(a,d)cyclohepten]-2-acetic acid, M.P. 142143 C.

(C) 3 trifluoromethyl 10',11 dihydrospiro[cyclopropane 1,5 5Hdibenzo(a,d)cycloheptene] 2- carboxylic acid A solution of 8.8 g. ofmethyl lithium in 1 1. of dry ether is stirred while 100 g. of3-trifluoromethyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-S-one isadded in portions, at a rate so that reflux is maintained. Afteraddition is completed the mixture is stirred and refluxed for two andone-half hours and then poured slowly into 1 l. of ice-water and 50 ml.of concentrated hydrochloric acid. The separated aqueous layer is washedwith ether and the combined ether solution is water-washed, dried andevaporated in vacuo to give 3-trifluoromethyl-5- methyl 10,11 dihydro 5Hdibenzo[a,d]cyclohepten- 5-ol.

A mixture of g. of the above alcohol and 300 ml. of dimethylsulfoxide isheated in an oil bath at 174 C. for 18 hours. The solution is pouredinto 2 l. of.- ice-water and extracted with ether. The extract iswater-washed, dried and evaporated in vacuo to give 3-trifluoromethyl- 5methylene 10,11 dihydro 5H dibenzo[a,d]-cycloheptene as an oil.

To a mixture of 0.6 g. of cupric sulfate in 250 ml. of

dry toluene, with stirring and refluxing, is added dropwise a solutionof 49 g. of the above S-methylene compound and 25 ml. of ethyldiazoacetate in 250 ml. ofi dry toluene. The reaction mixture is stirredand refluxed for one hour and an additional 15 ml. of ethyl diazoacetatein 100 ml. of dry toluene is added dropwise, with a subsequent addition30 minutes later. One hour after the final addition, with continuedrefluxing, the mixture is filtered and the filtrate evaporated in vacuoto give ethyl 3-trifluoromethyl 10,11dihydrospiro[cyclopropane-1,5-5H-dibenzo a,d cycloheptene 1-2-carboxylate.

A mixture of the above carboxylate in 500 ml. of ethanol and 30 g. ofpotassium hydroxide in 50 ml. of. water is stirred and refluxed for twohours, then evaporated in vacuo. The residue is dissolved in water,washed with ether and the aqueous solution acidified with concentratedhydrochloric acid. The acidic solution is extracted with ether and thedried extract is evaporated. The residue is triturated with 200 ml. ofmethylene chloride and cooled to C. to give3-trifluoromethyl-10',11-dihydrospiro [cyclopropane -1,5 5Hdibenzo(a,d)cycloheptene]-2- carboxylic acid.

Treatment of this carboxylic acid as outlined in part B above yields3-trifluoromethyl-10',11'-dihydrospiro [cyclopropane 1,5 5Hdibenzo(a,d)cycloheptene]- 2-acetic acid.

(D) X substituted 10,11 dihydrospiro[cyclopropane- 1,5 5Hdibenzo(a,d)cycloheptene] 2 carboxylic and -2-acetic acids By employingin part A above the following cycloheptenones (see for example Chem.Abs. 56 7241b; Chem. Abs. 57 16520i; Chem. Abs. 57 7197c), asillustrated in part C, With similar subsequent reaction as in part B,there are obtained corresponding carboxylic and acetic acid startingmaterials:

3-chloro-10,1l-dihydro-SH-dibenzo[a,dJcyclohepten- 3-lff I l 1 O-J1-dihydro-5H-dibenzo[a,d]cyclohepten- 3-rf1e tiiZxy-10, 1l-dihydro-SH-dibenzo [a,d] cyc1ohepten- 3-ri1 e i tizl- 1 0,1l-dihydro-SH-dibenzo [a,d] cyclohepten- 3-riie t li lthio-1O,1l-dihydro-SH-dibenzo [a,d] cyclohepten-S-one EXAMPLE 1 A mixture of 4.6g. ofi 10',11'-dihydrospiro[cyclopropane1,5' 5H dibenzo(a,d)cycloheptene[-2-acetic acid and 10 ml. of thionyl chloride is allowed tostand at room temperature for one hour, then heated at reflux for 30minutes, concentrated in vacuo and the residue stripped with toluene.The residual acid chloride is dissolved in 50 ml. of ether and addeddropwise to a solution of 4.5 g. of dimethylamine in 125 ml. of, ether.The mixture is stirred at room temperature for minutes, then refluxedfor one hour. A 40% aqueous solution of dimethylamine (50 ml.) is addedand the mixture stirred an additional 15 minutes. The separated organiclayer is washed with a saturated solution of sodium chloride, dried andconcentrated to give the 2-(N,N-dimethylacetamido)-10',11'-dihydrospiro[cyclopropane 1,5 5H dibenzo(a,d)cycloheptene] A suspensionof the above amide in 50 ml. of ether is added to a suspension 015 3.4g. of lithium aluminum hydride in 250 ml. of ether and the mixture isstirred and refluxed for two hours. After standing at room temperaturefor 12 hours, the reaction mixture is decomposed by the addition, insequence, of 3.5 ml. of water, 3.5 ml. of 10% sodium hydroxide solutionand 11 ml. ofi water, filtered and the filtrate concentrated in vacuo.The residue is distilled to give 2-(MN-dimethylaminoethyl)-10',11-dihydrospiro [cyclopropane-1,5' 5H dibenzo(a,d)-cyclo- 6 heptene], B.P.-170 C./0.3 mm.; hydrochloride salt, M.P. 191193 C.

Similarly, by employing in the above reaction sequence 4.4 g. of3'-methyl-l0,11'-dihydrospiro[cyclopropane- 1,5 5H dibenzo(a,d)cyclohepten]-Z-acetic acid there is obtained as a final product3'-methyl-2-(N,N-dimethylaminoethyl) 10,11'dihydrospiro[cyclopropane-1,5'- SH-dibenzo(a,d)cycloheptene].

EXAMPLE 2 To a mixture of 3.7 g. of 3-trifluoromethyl-10",11-dihydrospiro[cyclopropane 1,5 5H dibenzo(a,d)cycloheptene]-2-carboxylicacid and 3 ml. of triethylamine, cooled to 0 C., is added 2 ml. of ethylchloroformate in acetone. The mixture is stirred for 15 minutes and then4.4 g. of N-(ti-hydroxyethyl)piperazine in acetone is added withcooling. After stirring for three hours at room temperature, thereaction mixture is poured into cold water and extracted with ether. Thedried extract is evaporated to give3-trifluoromethyl-2-[N-(fl-hydroxyethyl) N piperazinoyl]10,11'dihydrospiro[cyclopropane-1,5-5H-dibenzo (a,d) cycloheptene] To asuspension of 1.0 g. of lithium aluminum hydride in ether is added asusension of 3.7 g. of the above piperazinyl derivative in ether and themixture stirred and refiuxed for eight hours. After standing overnightat room temperature, the reaction mixture is decomposed, filtered andthe filtrate acidified with ethanol-ethereal hydrogen chloride. Additionof excess ether precipitates the solid 3 trifluoromethyl 2 [N ([3hydroxyethyl) N'- piperazinylmethyl] 10',11 dihydrospiro[cyclopropane-1,5 5H dibenzo(a,d)cycloheptene]hydrochloride.-

Acetylation with acetyl chloride yields the corresponding,B-acetoxyethyl derivative.

EXAMPLE 3 A solution of 9.4 g. of3'-trifluoromethyl-10,11'-dihydrospiro[cyclopropane-1,5' 5Hdibenzo(a,d)cycloheptane1-2-acetic acid in acetone is treated with 7 ml.of triethylamine in acetone. The resulting mixture is cooled to 0 C. and5 ml. of ethyl chloroformate in acetone is added. After stirring for 20minutes, a solution of 7.1 g. of dimethylamine in acetone is added andstirring continued for 30 minutes with cooling and then for two hours atroom temperature. The reaction mixture is poured into ice-water,extracted with methylene chloride and the dried extract evaporated. Theresidue is taken up in ether, extracted with 10% sodium hydroxidesolution and the dried ether solution evaporated to give the solid3'-trifluoromethyl-2-(N,N-dimethylacetamido)-10',11'-dihydrospiro[cyclopropane1,5 5H- dibenzo (a,d cycloheptene] To 2.5 g. of lithium aluminum hydridein ether is added a solution of 9.4 g. of the above acetamido derivativein ether and the mixture is stirred and refluxed for eight hours. Afterstanding at room temperature overnight, the reaction mixture isdecomposed, filtered and the filtrate evaporated. The residue is takenup in ethanol and treated with ethereal hydrogen chloride. Addition ofexcess ether precipitates the 3-trifluoromethyl-2-(N,Ndimethylaminoethyl) 10,1'1' dihydrospiro[cyclopropane-1,5 -5H-dibenzo(a,d) cyclohepten] hydrochloride.

Similarly, by employing 11 g. of pyrrolidine or 13 g. of piperidineinstead of dimethylamine in the above reaction sequence with subsequentreduction by 2.5 g. of lithium aluminum hydride there is obtained3'-trifiuoromethyl-2-(N-pyrrolidinylethyl) 10',11 dihydrospiro[cyclopropane-l,5-5H-dibenzo(a,d)cycloheptene] or 3-trifluoromethyl-2-(N-piperidinylethyl) 10',11' dihydrospiro[cyclopropane-l,5-5H-dibenzo(a,d) cycloheptene] EXAMPLE 4 To asuspension of 22 g. of10,11-dihydrospiro[cyclopropane-1,5-5H-dibenzo(a,d)cycloheptene] 2carboxlyic acid in 200 ml. of actone is added 19 ml. of triethylstirredfor 30 minutes. A solution of 16 g. of dimethylamine in 80 ml. ofacetone is added over 45 minutes, maintaining the temperature below C.After 30 minutes the reaction mixture is stirred at room temperature forone hour, then 15 minutes at 40 C., and poured into ice-water. Themixture is extracted with methylene chloride and the dried extractevaporated to give 2- (N,N dimethylcarboxamido) 10,l1' dihydrospiro-[cyclopropane-1,5-H-dibenzo(a,d)cycloheptene], M.P. 187190 C.

A solution of 27 g. of the above carboxamido derivative in 225 ml. ofether is added to a suspension of 8 g. of lithium aluminum hydride inether and the mixture refluxed for five and one-half hours. The reactionmixture is decomposed, filtered and the filtrate evaporated to give asolid which is dissolved in acetone. Ethereal hydrogen chloride is addedto the acetone solution to yield 2-(N,N-dimethylaminomethyl) ',11'dihydrospiro[cyclopropane 1,5 5H dibenzo(a,d)cycloheptene1hydrochloride,M.P. 235237 C.

Similarly, by employing 33 g. of N-methylpiperazine instead ofdimethylamine in the above reaction sequence, the corresponding2-(N-methyl-N-piperazinylmethyl)- 10',11-dihydrospiro[cyclopropane 1,55H dibenzo- (a,d)cycloheptene] is obtained.

EXAMPLE 5 To a solution of 5.9 g. of3'-chloro-10',11'-dihydrospiro[cyclopropane 1,5 5Hdibenzo(a,d)cycloheptene]-2-carboxylic acid in 60 ml. of acetone, cooledto 0 C. is added 4.7 ml. of triethylamine in acetone and 3.2 ml. ofethyl chloroformate. The mixture is stirred for minutes and then asolution of 2.6 g. of sodium azide in water is added. After stirring for30 minutes, the reaction mixture is poured into ice-water and extractedwith toluene. The dried extract is heated on the steam bath to decomposethe acid azide. Removal of the solvent gives the residual isocyanatederivative.

To a stirred mixture of 50 ml. of 3 M methyl magnesium bromide in etheris added 6.8 g. of the above isocyanate in ether. The mixture isrefluxed for two hours, cooled and 200 ml. of 10% hydrochloric acidsolution is added slowly. The separated aqueous layer is extracted Withether. Concentration of the organic solutions gives3'-chloro-5-(N-acetylamino) 10,11 dihydrospiro[cyclopropane- 1,5'-5H-dibenzo (a,d) cycloheptene] To a solution of 7.1 g. of the aboveN-acetylamino derivative in 70 m1. of tetrahydrofuran is added 1.0 g. of53.5% sodium hydride and the mixture is stirred and refluxed for onehour. A solution of 8 ml. of ethyl iodide in 25 ml. of tetrahydrofuranis added to the cooled reaction mixture which is then refluxed for fourhours. An additional 8 ml. of ethyl iodide in 10 ml. of tetrahydrofuranis added and refluxing continued for 12 hours. The reaction mixture isfiltered and the filtrate concentrated in vacuo. The residue is taken upin water and ether, extracted with ether and the dried solvent removedto give3'-chloro-2-(N-acetyl-N-ethylamino)-10',11-dihydrospiro[cyclopropane 1,55H dibenzo(a,d)cycloheptene].

A solution of the above N-acetyl-N-ethylamino derivative (7.6 g.) inether is added to a suspension of 5.0 g. of lithium aluminum hydride inether and the mixture stirred and refluxed for six hours. Decompositionof the metal complex yields an oil which is treated in acetone solutionwith ethereal hydrogen chloride to give 3-chloro-2-(N,N-diethylamino)l'0',11 dihydrospiro- [cyclopropane 1,5 5H dibenzo(a,d)cycloheptene]hydrochloride.

Direct hydrolysis of the above isocyanate derivative yields3'-chloro-2-amino 10,11' dihydrospiro[cyclopropane-1,5'-5H-dibenzo (a,d)cycloheptene].

8 EXAMPLE 6 To a suspension of 4 g. of lithium aluminum hydride in etheris added a solution of 9.6 g. of 3'-chloro-2- (N-acetylamino) 10,11dihydrospiro[cyclopropane- 1,5-5H-dibenzo(a,d)cycloheptene] (prepared asdescribed in Example 5) in ether and the mixture stirred and refluxedfor eight hours. The reaction mixture is decomposed, filtered and thefiltrate evaporated to give 3'-chloro-2-(N-monoethylamino) 10,l1dihydrospiro- [cyclopropane-1,5-5H-dibenzo(a,d) cycloheptene] EXAMPLE 7To a suspension of 9.0 g. of 10,ll'-dihydrospiro[cyclopropane-1,5'5H-dibenzo(a,d) cycloheptene]-Z-carboxylic acid in 60 ml. of acetone isadded 8 ml. of triethylamine in acetone, cooled to 5 C., 6 ml. of ethylchloroformate in acetone is added and the mixture is stirred for 15minutes in the cold. A solution of 4.4 g. of sodium azide in Water isadded, stirred for 30 minutes, poured into ice-water and extracted withtoluene. The dried extract is heated until gas evolution ceases and thenthe solvent is removed to give the corresponding isocyanate derivative.The latter (11.7 g.) is dissolved in 60 ml. of ethanol and stirred andrefluxed for two hours. Removal of the solvent in vacuo gives the ethylcarbamate derivative.

A solution of 10.0 g. of the above carbamate in 50 ml. ofdimethylsulfoxide is added to a suspension of 1.4 g. of 55.6% sodiumhydride (mineral oil) in 35 ml. of dimethylsulfoxide. The mixture isheated briefly, cooled to 20 C. and 7 ml. of methyl iodide is added,maintaining the temperature between 15-20 C. This mixture is heated at5560 C. for 30 minutes, poured into 250 ml. of ice-Water, extracted withether and the dried extract evaporated to give Z-(N-methyl Ncarbethoxyamino)-10',11'-dihydrospiro[cyclopropane 1,5 5H-dibenzo a,d)cycloheptene] To a suspension of 2.5 g. of lithium aluminum hydride inether is added a solution of 10.1 g. of the above N-methyl carbamatederivative in ether and the mixture is refluxed for four hours. Thereaction mixture is decomposed, filtered, and the ether removed to give2-(N,N- dimethylamino)-l0',11'-dihydrospiro[cyclopropane 1,5-5H-dibenzo(a,d)cycloheptene] which is converted to the hydrochloridesalt, M.P. 221225 C.

Similarly, 3 '-methylthio-10',1 l'-dihydrospiro[cyclopropane-1,5'-5H-dibenzo (a,d) cycloheptene] 2-carboxylic acidyields 3-methylthio-2-(N,Ndimethylamino)-10",1l-dihydrospiro[cyclopropane 1,55H-dibenzo(a,d)-cycloheptene].

EXAMPLE 8 To a suspension of 29 g. of 3'-bromo-10,l1-dihydrospiro[cyclopropane-1,5 SH-dibenzo a,d) cycloheptene] 2-acetic acid in 200 ml.of acetone is added 19 ml. of triethylamine in acetone. The mixture iscooled to 5 C., 14 ml. of ethyl chloroformate in acetone is added andstirred for 30 minutes. A solution of 16 g. of dimethylamine in ml. ofacetone is added over 45 minutes, maintaining the temperature below 0 C.After 30 minutes the reaction mixture is stirred at room temperature forone hour, then 15 minutes at 40 C. and poured into ice-water. Themixture is extracted with methylene chloride and the dried extractevaporated to give 3- bromo-2-(N,Ndimethylacetamido)-10,11-dihydrospiro- [cyclopropane- 1 ,5 -5H-dibenzoa,d cycloheptene] A solution of 35.2 g. of the above acetamidoderivative in 225 ml. of ether is added to a suspension of 8 g. oflithium aluminum hydride in ether and the mixture refluxed for sixhours. The reaction mixture is decomposed, filtered and the filtrateevaporated to give 3-bromo-2-(N,Ndimethylaminoethyl)-10'-11'-dihydrospiro[cyclopropane-l ,5'-5H-dibenzo(a,d cycloheptene].

Similarly, by employing in the above reaction sequence 28.7 g. of3-methoxy-10',ll-dihydrospiro[cyclopropane 1,5'-5Hdibenzo(a,d)cycloheptene]-2-acetic acid there is obtained as a finalproduct 3-methoxy-2- (N,N-dimethylaminoethyl) 10-11'dihydrospiro[cyclopropane-1,5'-5I-I-dibenzo a,d) cycloheptene] What isclaimed is:

1. A chemical compound selected from the group consisting of a free baseand a pharmaceutically acceptable salt thereof, said free base havingthe formula:

in which:

R is hydrogen, chlorine, bromine, trifluoromethyl,

methyl, methoxy or methylthio; n is an integer of from 0 to 2; and R andR taken together with the nitrogen atom to which they are attached,represent a pyrrolidine, N- methylpiperazine,N(B-hydroxyethyl)-piperazine or N(fl-acetoxyethyl)-piperazine ring. 2. Achemical compound in accordance with claim 1 in which R and R takentogether with the nitrogen atom to which they are attached, represent anN-methylpiperazine ring.

3. A chemical compound in accordance with claim 2 in which n is 1.

4. A chemical compound in accordance with claim 3 in which R ishydrogen.

5. A chemical compound in accordance with claim 1 in which R and R takentogether with the nitrogen atom to which they are attached, represent anN'-(,B-hydroxyethyD-piperazine ring.

6. A chemical compound in accordance with claim 5 in which n is 1.

7. A chemical compound in accordance with claim 6 in which R is3'-trifluoromethyl.

References Cited UNITED STATES PATENTS 3,309,404 3/1967 Engelhardt260-293 X 3,335,133 '8/1967 Kaiser et al. 260-239 3,340,268 9/ 1967Mizzoni 260293 X 3,395,151 7/1968 Kaiser et al. 260279 DONALD G. DAUS,Primary Examiner US. Cl. X.R.

